The clinical recognition of venous and arterial thromboembolic disorders is unreliable, lacking in both sensitivity and specificity. In light of the potentially life threatening situation, the need to rapidly diagnose thromboembolic disorders using a non invasive method is an unmet clinical need. Platelet activation and resulting aggregation has been shown to be associated with various pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders such as unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury. See generally, Fuster et al., JACC, Vol. 5, No. 6, pp. 175B-183B (1985); Rubenstein et al., Am. Heart J., Vol. 102, pp. 363-367 (1981); Hamm et al., J. Am. Coll. Cardiol., Vol. 10, pp. 998-1006 (1987); and Davies et al., Circulation, Vol. 73, pp. 418-427 (1986). Recently, the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), has been identified as the membrane protein which mediates platelet aggregation by providing a common pathway for the known platelet agonists. See Philips et al., Cell, Vol. 65, pp. 359-362 (1991).
Platelet activation and aggregation is also thought to play a significant role in venous thromboembolic disorders such as venous thrombophlebitis and subsequent pulmonary emboli. It is also known that patients whose blood flows over artificial surfaces, such as prosthetic synthetic cardiac valves, are at risk for the development of platelet plugs, thrombi and emboli. See generally Fuster et al., JACC, Vol. 5, No. 6, pp. 175B-183B (1985); Rubenstein et al., Am. Heart J., Vol. 102, pp. 363-367 (1981); Hamm et al., J. Am. Coll. Cardiol., Vol. 10, pp. 998-1006 (1987); and Davies et al., Circulation, Vol. 73, pp. 418-427 (1986).
A suitable means for the non-invasive diagnosis and monitoring of patients with such potential thromboembolic disorders would be highly useful, and several attempts have been made to develop radiolabeled agents targeted to platelets for non-invasive radionuclide imaging. For example, experimental studies have been carried out with 99mTc monoclonal antifibrin antibody for diagnostic imaging of arterial thrombus. See Cerqueira et al., Circulation, Vol., 85, pp. 298-304 (1992). The authors report the potential utility of such agents in the imaging of freshly formed arterial thrombus. Monoclonal antibodies labeled with 131I and specific for activated human platelets have also been reported to have potential application in the diagnosis of arterial and venous thrombi. However, a reasonable ratio of thrombus to blood (target/background) was only attainable at 4 hours after the administration of the radiolabeled antibody. See Wu et al., Clin. Med. J., Vol. 105, pp. 533-559 (1992). The use of 125I, 131I, 99mTc, and 111In radiolabeled 7E3 monoclonal antiplatelet antibody in imaging thrombi has also been recently discussed. Coller et al., PCT Application Publication No. WO 89/11538 (1989). The radiolabeled 7E3 antibody has the disadvantage, however, of being a very large molecular weight molecule. Other researchers have employed enzymatically inactivated t-PA radioiodinated with 123I, 125I and 131I for the detection and the localization of thrombi. See Ordm et al., Circulation, Vol. 85, pp. 288-297 (1992). Still other approaches in the radiologic detection of thromoboembolisms are described, for example, in Koblik et al., Semin. Nucl. Med., Vol. 19, pp. 221-237 (1989).
Arterial and venous thrombus detection and localization is of critical importance in accurately diagnosing thromboembolic disorders and determining proper therapy. New and better radiolabeled agents for non-invasive radionuclide imaging to detect thrombi are needed. The present invention is directed to this important end.